Dr. Michael Patrick Boyle is an Assistant Professor in the Pulmonary and Critical Care Division of the Johns Hopkins School of Medicine. He is fully committed to an academic career investigating genotype and phenotype relationships in cystic fibrosis (CF). The mentor of this application, Dr. Garry Cutting, is a world-recognized expert in the genetics of CF, professor and director of graduate education at the McKusick-Nathans Institute of Genetic Medicine, and previous mentor of numerous successful K awards. The didactic and mentoring program outlined in this application is the result of close collaboration between Dr. Boyle and Dr. Cutting and will provide the foundation for Dr. Boyle's development as an independent investigator. CF is caused by mutations in the chloride channel CFTR. A wide range of severity of pulmonary disease is seen in CF individuals with identical CFTR genotypes, making it clear that CFTR genotype is not the main determinant of severity of CF lung disease. The overall goal of this proposal is to help identify the basis for variability of CF lung disease in individuals with identical CFTR genotype. We aim to answer: Do genes which modify the severity of CF lung disease exert their influence by altering the level of expression and function of CFTR, or through mechanisms unrelated to the underlying CFTR defect (e.g. inflammatory mediators, airway defense)? To do this we will determine if there is a difference in CFTR expression and function in the airway epithelium of homozygous delta F508 CF patients with mild and severe lung disease. First, we will use Nasal Potential Difference Measurement, the most sensitive in-vivo measurement of the ion-transport function of CFTR, to determine if there are differences in CFTR ion-transport. Second, because some cellular functions of CFTR are not reflected in these ion transport measurements, we will evaluate for differences in CFTR expression by comparing mRNA levels. These ion-transport and mRNA studies should allow us to determine if variability in CF lung disease is associated with alterations in level of expression and function of CFTR. Last, we will evaluate three of the strongest current CF candidate modifier genes to determine if the distribution of their functional alleles segregates with severity of lung disease in our CF clinic population.